November 17, 2011

Well, technically that title should be PROTON, ELECTRON, and Hepatitis C, the first two words being the names of two recent studies of PSI-7977, a potential new drug for treating hepatitis C virus (HCV).

The Latest Findings

There’s a lot to talk about with PSI-7977—mainly in light of study results presented a few days ago at the 62nd Annual Meeting of the Association for the Study of Liver Diseases (AASLD) in San Francisco. So let’s get the elephant in the room out of the way before we go any further: I do not know what POSITRON and ELECTRON stand for. Nor do I know what FISSION, PROTON, and ATOMIC stand for—but more on that later. All I can tell you is that at some point in the history of drug development, pharmaceutical companies and/or clinical trial cooperative groups decided that acronyms were necessary or advantageous for some reason, paving the way for many a BLT, BOLERO and COMFORT for years to come.

PSI-7977 is kind of exciting. In the PROTON study, this drug, a nucleotide analog, was combined with the then-standard of care, pegylated interferon plus ribavirin. (Since PROTON was done, telaprevir and boceprevir were approved, changing the standard of care.) In PROTON, 96% of patients had a sustained virologic response (SVR), which is the measure of cure for HCV. Now, to balance this, is a wonderful moment of parsing the data: 96% is impressive, no doubt, but it has to be mentioned that the total number of patients in that study was 25, with 24 patients being actually evaluable. It was an early-phase study, so that small number of patients is not unusual, but most reports about the latest PSI-7977 results are highlighting that initial 96%, and it’s hard to find the actual N of the study. Here is a PDF of the full report of the PROTON study.

After PROTON delivered its encouraging results, Pharmasset, the maker of PSI-7977, launched ELECTRON, a phase II study in which a number of patients were given the experimental drug plus ribavirin. And that is the key: 10 of the enrollees received NO pegylated interferon. And guess what: the combination worked. All 10 of those HCV patients had an SVR.

Now, a couple of things to explain. First, these were patients with genotype 2 or 3 HCV. The reason why these genotypes were selected is because they tend to be highly responsive to interferon. Wait – so, why were those the people who were not given interferon? Well, the logic was that if PSI-7977 plus ribavirin didn’t work, those patients could be more easily rescued with a course of pegylated interferon + ribavirin than HCV patients with, say, genotype 1, the most difficult to treat variety of the disease. As it turned out, that rescue therapy wasn’t needed, but still, the logic is interesting when it comes to understanding drug trials.

Another important point is why eliminating interferon from treatment could be useful. There are two reasons. First, some patients respond to interferon and others do not. As it turns out, variations in the IL28B gene are behind that likelihood (or lack thereof), a discovery that has its own fascinating story. (Here’s a link to an article I wrote about it for Science last year.) David Goldstein, of Duke University, was instrumental in this finding, as was David Thomas, director of the Division of Infectious Diseases at Johns Hopkins School of Medicine, a man whose work with HCV, along with hepatitis B and other illnesses, extends from the genetic aspects to the public health injustices surrounding screening and care.

The second point about interferon is that it’s not for everyone, even those who do respond physically. The drug causes harsh side effects, including mood disorders, to the point where some patients, such as those who are clinically depressed at the time of their diagnosis, may not be candidates for treatment, even if they have the IL28B variant that indicates they’d likely respond to the drug. In short, many researchers and drug developers have been working on finding a way to treat HCV without pegylated interferon. The ELECTRON study is the first (as far as I know) to do it.

In the ELECTRON study, alongside those 10 patients given PSI-7977 + ribavirin were three other groups of patients, each of which was given a different schedule of PSI-7977 + ribavirin + pegylated interferon. All of the patients responded well. The outcomes among the patients not given pegylated interferon were the same as for those given that drug. The difference was that patients in the three-drug groups experienced at least one side effect more often (any of the following: headache, fatigue, depression, insomnia, anxiety, irritability, muscle soreness, upper respiratory tract infections), as well as a greater occurrence of moderate-to-severe drops in neutrophils, a type of white blood cell.

Several new treatment arms have been added to the ELECTRON study, including one in which patients will be given PSI-7977 alone. All of the patients are still genotype 2/3 only.

Another word about the genotype selection. Telaprevir (Incivek) and bocepevir (Victrelis) were both approved for genotype 1 HCV. These drugs are highly effective, and while they won’t cure all patients, they will cure many. So it may be that the drug maker behind PSI-7977 is focusing on a different genotype for marketing purposes. That being said, the phase III clinical trial program will include three studies, one of which will focus on genotype-1 patients. The other two soon-to-be-launched studies (the aforementioned FISSION and POSITRON) will evaluate PSI-7977 + ribavirin in more than 700 patients with genotype 2/3 HCV, according to a recent statement from Pharmasset. And we mustn’t forget the other ongoing study, ATOMIC, a phase IIb study in which 300 patients with chronic HCV genotype 1 are being given the three-drug combo for either 12 or 24 weeks, and 25 patients with genotype 4, 5, 6 or an indeterminate genotype will receive the same medications for 24 weeks.

Other New Drugs for Hepatitis C

If HCV were a party, this would be the point at which the room starts getting a touch crowded; not so much that you have to leave, but definitely to the point where there are no seats left. For although PSI-7977 has got the makers of telaprevir a little concerned about its future earnings, several other compounds, many of which may also work without pegylated interferon, are currently being studied. These include:

• Nonnucleoside polymerase inhibitors (which, for the technically minded among you, seem to exert their effect by “allosteric inhibition of the NS5B HCV polymerase,” according to Ira Jacobson, commenting in Gastroenterology & Hepatology, in October 2010.)

• Cyclophilin antagonists, drugs that target the host cell rather than the virus. Cyclophilin is a protein that the virus uses in the replication of RNA. One of the reasons why this approach could gain traction is because it eliminates concern about the virus becoming resistant to treatment, a feature that warrants having as many treatment options as possible, meaning that it’s probably good that this party is getting crowded.

• Alternatives to pegylated interferon are also being investigated. For example, albumin interferon alfa-2b and pegylated interferon lambda are two candidates. Loteron is an interferon alpha product that could work, and consensus interferon, which is nonpegylated, was already approved for patients who don’t respond to pegylated interferon plus ribavirin.

HCV and the History of the Human Race

On another, related note, we all come across certain topics where we feel like the trajectory of the story somehow encapsulates all there is to understand about human life, or some other big picture for which this smaller story serves as a microcosm. For me, HCV is one of those stories. This current chapter is not only illuminating so much about the best of modern drug development, but also reveals many of the problems still not being adequately addressed, like screening and prevention (HCV is primarily transferred through dirty drug needles), and the fact that many HCV patients are still not treated until late in the disease, one of the reasons why being a passing of the buck going on at the level of insurance. There is also the question (warning: idealist alert) of whether we will ever come to the day when people won’t feel the need to inject recreational drugs, dirty needle or not, and eliminating, or at least severely shrinking, HCV as a concern once and for all.

But then there is a whole trace of human history—steps and missteps—in the story of HCV. The geographic distribution of genotypes is a starting point for a rich and harrowing look at how viruses move across the world. For example, one of the ways that hepatitis was spread through Egypt was through a campaign against schistosomiasis along the Nile delta in the 1960s. (Here is one interesting PDF on that.) It was a well-intentioned and needed public health measure but the needles weren’t sterilized and so as people were treated for the parasite, village by village, the virus made its way around. Egypt currently has the highest rates of HCV in the world. Anti-malaria campaigns in Cameroon had a similar impact.

Also fascinating is the fact that the spread of the virus can be traced across slave trade routes from Africa to Europe. And, as Oliver Pybus, an evolutionary biologist at Oxford University, points out, that fact brings up another central mystery about HCV, which is that the virus has been around for thousands of years, but the most common modes of transmission that we know of are connected to relatively modern inventions (blood transfusions and needles to inject drugs). “What is clear is that this endemic transmission was occurring across the whole of Sub-Saharan Africa and Asia and it doesn’t seem right that it would be maintained by very culturally-defined and location-specific routes of transmission,” Pybus once told me. In other words, as he explained, practices like scarification and tattooing could account for some, but not all, of the spread of HCV in that time and place. Making his insights even more fascinating is the fact that Pybus has managed to use genome sequencing and computer programs to trace the phylogenetic tree of HCV that extends over thousands of years. (Pybus was the WHO’s point person on tracking the origin of swine flu a few years back because of the software and methods he’s invented.)

Then there is the question of how HCV got into humans in the first place. Columbia University virologist Ian Lipkin recently shed some fascinating light on this question when he found a genetic homolog of HCV in dogs. Here’s a tiny bit from me on that (scroll to bottom), and a lot more about it from Carl Zimmer.

You see? There is a whole trace of history inside the story of HCV. With all of the issues that tend to get our dander up when it comes to drug development (and those exist with HCV, too), here is one that piques our fascination and curiosity.

There is one more looming question. When it comes to the increasing number of HCV medications: why now? We know that pharmaceutical companies are businesses, so obviously there is money to be made in creating new drugs for HCV. Has there been some recent dawning realization about this? Are drug makers for some reason now guaranteed a solid return on the investment, whereas they weren’t some years back? Or is it more due to the science and advances in HCV research that have led to so many new targets to investigate?

Clearly, there is at least one more chapter waiting to be written in this compelling story, and I’m sure many more beyond that.

The data, presented here at The Liver Meeting 2011: American Association for the Study of Liver Diseases (AASLD) 62nd Annual Meeting, suggest that greater surveillance for HBV and safer hematologic-sparing treatments for HCV are required.

In the first study, lead investigator Jessica P. Hwang, MD, MPH, and colleagues looked at HBV reactivation during cancer treatment using a retrospective dataset from her institution. "This is a topic that is gaining momentum in public health, oncology, as well as hepatology landscapes," she explained. However, because of the lack of large population-based studies, the current prevalence of HBV reactivation in patients undergoing cancer treatment is unclear. "Our goals were to determine the prevalence and predictors of HBV screening and reactivation in a comprehensive cancer center."

What is known is that HBV reactivation can occur at anytime during chemotherapy or after chemotherapy, during the recovery phase of the immune system's reconstitution. "This can lead to poor outcomes, hepatic flares, liver failure, and death," Dr. Hwang said. "It's important to identify these patients accurately so that effective oral antiviral therapy can be initiated."

The study by Dr. Hwang and colleagues explored 2 issues: the existence of inconsistent guidelines for screening cancer patients for HBV, and the lack of adherence to the guidelines that are in place.

The 3 entities that have addressed HBV and cancer are the Centers for Disease Control and Prevention (CDC), the AASLD, and the Association of Clinical Oncology (ASCO).

On screening and treatment, the CDC and AASLD recommendations are in agreement: All patients with cancer who are about to undergo immunosuppressive therapy should be tested for HBV and screened for hepatitis B surface antigen (HBsAg), hepatitis B core antigen (anti-HBc), and antibodies against HBsAg (anti-HBs). If there is a positive test result, HBV prophylaxis should be initiated.

Recommendations from ASCO are less comprehensive: Only those about to undergo "highly" immunosuppressive regimens (i.e., stem cell transplants or treatment with rituximab) and patients "at risk" for HBV should be tested, and screening should only be for HBsAg and anti-HBc (recommended treatment is the same).

"Although there is agreement on the importance of antiviral prophylaxis, ASCO does not advocate the use of all 3 screening tests," Dr. Hwang noted. Furthermore, the ASCO guidelines require that oncologists be aware of the risk factors for HBV infection, and that they take the time to actually perform HBV screening. The discrepancies in recommendations led Dr. Hwang's team to examine current practices at the M.D. Anderson Cancer Center.

The retrospective chart review gathered data on screening, positive tests, and HBV reactivation for all chemotherapy-naïve cancer patients seen at the M.D. Anderson over a 4-year period. Evidence of viral reactivation was defined as an alanine aminotransferase (ALT) level of at least 100 U/L plus total bilirubin of at least 2.5 mg/dL; detectable HBV levels when HBV was previously undetectable; or HBV DNA of at least 100,000 copies/mL.

The screening period was 2 months before the first or second round of chemotherapy. Both solid tumor and hematologic malignancies were considered. Risk factors for HBV prior to screening included International Classification of Diseases, Ninth Revision (ICD-9) codes for HCV, HIV, liver disease, and hepatitis.

Approximately 71,000 charts were reviewed. Of the 10,729 patients receiving potentially immunosuppressive chemotherapy, Dr. Hwang and colleagues found that only 1787 patients (17%) were screened for HBV. Tests used were HBsAg (1665 patients); HBsAg and anti-HBC (87 patients); and anti-HBc (35 patients). "If we just look at the patients with HBV risk factors, only 1 of 5 patients were screened," Dr. Hwang reported.

Of those screened, 34 patients were found to have HBV reactivation. Fourteen of the 34 were found to have chronic HBV infection, and anti-HBc was detected in 20 patients. Of the total reactivation cohort, 23 patients had hematologic cancers, 11 had solid tumors, and 10 had been treated with rituximab.

Predictors of those chosen for screening were being male, having HBV risk factors, having a hematologic malignancy, and the use of rituximab. Predictors of HBV reactivation were being male, being Asian or black, and having HBV risk factors. "Interestingly, Asian and black race did not predict screening, yet they were more often testing positive," said Dr. Hwang.

Most striking was the lack of use of HBV therapy after a positive test. Of the 34 patients, 9 received prophylaxis (2 later died), 11 received treatment after HBV reactivation (8 died), and 14 received no treatment (10 later died).

"It does not appear that we are following the CDC and AASLD recommendations," Dr. Hwang pointed out, adding that M.D. Anderson is not even adhering to ASCO recommendations.

"Preventable reactivation does occur, is occurring, and prophylaxis has been shown to dramatically reduce mortality in cancer patients with HBV," she explained.

HCV Reactivation

A study from the same institution looked at HCV reactivation in patients who had undergone treatment with rituximab and gemcitabine. In this retrospective chart review, investigators looked at the records of 308 HCV-infected patients treated at M.D. Anderson over a 1-year period. HCV exacerbation was defined as a greater than 3-fold increase in ALT in the absence of hepatotoxic drugs, systemic coinfection, recent blood transfusions, and tumor infiltration of the liver.

"We found that 11% of patients who received this chemotherapy developed reactivation of HCV," reported coinvestigator Harrys Torres, MD, assistant professor of infectious diseases at M.D. Anderson. "Interestingly, none of these patients died with liver failure, which is different than with HBV reactivation."

What concerns Dr. Torres is that HCV reactivation necessitates discontinuation of chemotherapy. "We have to stop chemo in 50% of cases," he said. "It seems that HCV reactivation does not compromise the patient from the biologic standpoint, but from the oncologic standpoint, with treatment interruptions," it does.

Treating HCV concurrently with the administration of chemotherapy is not an option. "Current HCV agents are associated with anemia and neutropenia, and these patients already have some sort of hematologic toxicity with the chemotherapy," Dr. Torres said. "In the near future, we're hoping to see new drugs that can be given orally once a day that would allow chemotherapy to continue."

Although hepatocellular carcinoma (HCC) does not garner the type of publicity breast cancer and colon cancer receive, it clearly remains a major cause of cancer mortality.

In the United States, the incidence of liver cancer remains the fifth and ninth leading cause of cancer deaths in men and women with an estimated 13,260 male and 6,330 female deaths in 2011. In contrast to the incidences of colon, lung and breast cancer, which are decreasing, the incidence of liver cancer is increasing.1

Studies (Davila et al, Gastroenterology, 2004) indicate this is in part due to the large number of people infected with viral hepatitis. Because of the latency between viral infection, cirrhosis, and the development of cancer, it has been projected that the number of hepatitis C related liver cancer cases will continue to rise and potentially double over the next 10-20 years (reviewed by El-Serag, Hepatology 2002).

The American Association for the Advancement of Liver Disease (AASLD) has developed recommendations for screening populations at risk. For chronic hepatitis B carriers, the guidelines recommend screening Asian males forty years of age or older, Asian females 50 years of age or older, all hepatitis B carriers with cirrhosis, all hepatitis B carriers with a family history of HCC and African hepatitis B carriers older than 20. Screening should also be offered to patients with cirrhosis related to hepatitis C, alcohol, hemochromatosis, and primary biliary cirrhosis.

Because patients who develop hepatocellular cancer often have cirrhosis as well, treatment algorithms and tumor staging systems have been developed to try to incorporate the degree of hepatic dysfunction in the recommendations for treatment.

For example, the treatment recommendation for a patient with a small tumor but with advanced cirrhosis may be different than a patient with the same size tumor but much better liver function and reserve. Multiple staging systems have been described to try to determine the best way to segregate patients to the appropriate treatment algorithm. One current commonly used algorithm is the Barcelona Clinic Liver Cancer (BCLC) staging classification. This staging system, Fig 1, takes into account underlying liver function as represented by the patient’s Child-Pugh-Turcotte score, as well as, tumor size, vascular involvement, the presence of extrahepatic disease and the patient’s performance status.

Multiple tools have been added to the armamentarium for the treatment of hepatocellular cancers. These can be separated into three categories: surgical, medical and radiological. Surgical options include resection, ablation and transplantation.

In a patient with HCC and no underlying cirrhosis, the goal should be resection if possible. In a study by Llovet et al. (Hepatology 1999), excellent five year survival rates were reported (74%) for patients with a normal bilirubin and no portal hypertension who were treated with resection. Arii et al. (Hepatology 2000) reported similar survival rates for 1,318 patients who underwent resection for the treatment of small (< 2 cm) hepatocellular cancers.

Most patients with hepatocellular cancers and early stage tumors are not candidates for resection based on poor underlying liver function and inadequate liver reserve. Based on a publication by Mazzaferro et al. (NEJM 1996) the United Network for Organ Sharing, UNOS, currently gives special consideration to patients who have a liver cancer that is less than 5 cm in size or have three or fewer tumors, no individual tumor larger than 3 cm. These criteria have become known as the Milan criteria. Patients that satisfy these requirements can be placed on the transplant list and are awarded enough points that they can often be transplanted relatively quickly. In Ohio they often can be transplanted within 3-6 months. Transplant recipients who met Milan criteria were found to have a 75% four year survival.

Ablation may be a possible treatment for patients with small tumors, < 3 cm, with hepatic dysfunction severe enough to preclude them from resection. This treatment modality employs either cold (cryoablation) or heat (radiofrequency/microwave) to destroy tumors. Interventional radiologists and radiation oncologist also have effective treatments which can be offered to appropriate candidates.

Within the last several years, sorafenib, a multiple kinase inhibitor, was FDA approved for the treatment of unresectable hepatocellular carcinoma. In a randomized control trial, sorafenib was shown to increase survival over best supportive care.

With so many options now available for the treatment of hepatocellular carcinoma, trials are now underway to evaluate the effect of combining various treatments to obtain better long term survival. In addition, efforts are underway to educate the general population on the importance of screening high risk groups at regular intervals. By finding cancers earlier and having multiple tools to treat patients, new found hope has been given to curing this disease.

PHILADELPHIA -- Hepatitis C virus (HCV) infection is associated with an increase in mortality in patients on hemodialysis, but treatment is rare in that population, researchers found.

In a large, international cohort study of patients on hemodialysis, only one in every 100 of those who were HCV-positive received antiviral treatment, according to David Goodkin, MD, of the Arbor Research Collaborative for Health in Ann Arbor, Mich.

Treatment of HCV infection was associated a 73% lower risk of dying during follow-up, even after accounting for numerous potential confounders (HR 0.27, 95% CI 0.08 to 0.92), he reported at the American Society of Nephrology meeting here.

"We may be doing a disservice to our hemodialysis patients by not treating HCV, particularly those who are awaiting transplantation," Goodkin said.

A randomized trial examining the effect of treating HCV infection in patients on hemodialysis has not been done, and Goodkin said such a trial is unlikely because all previous trials of HCV treatments have excluded patients with renal failure.

But even if such a trial is undertaken, it would be years before conclusions could be drawn, he said.

"In the interim, clinicians are going to go on rounds, 10% of the patients are HCV-positive, and I really hope, at least for the transplant waiting list patients, [clinicians will] think again about whether [the patients] should be treated or not."

The findings came from a data analysis of the Dialysis Outcomes and Practice Patterns Study (DOPPS), a prospective cohort study of patients at 382 randomly selected hemodialysis clinics in 12 countries.

The current study included information on 47,004 patients participating in the study between 1996 and 2011. Median follow up ranged from 0.94 to 1.76 years.

The overall prevalence of HCV infection -- determined by a diagnosis of HCV infection in the medical record or a positive test for HCV antibodies at baseline or during follow-up -- was 9.6%, indicating that "this is not a trivial problem," according to Goodkin.

Overall, only 47 patients in the study (1.1% of those who were HCV-positive) were receiving antiviral medications. For patients on the kidney transplant waiting list who were HCV-positive, 3.8% were receiving antivirals.

Goodkin acknowledged that it is possible the use of antiviral medications was underestimated, but said that after calling some of the hemodialysis centers, he trusted the figures.

"Even if we were off by a factor of three, it's still almost no one is being treated," he said.

That is particularly important because HCV infection is associated with a 22% increased risk of mortality after adjustment for patient characteristics (HR 1.22, 95% CI 1.11 to 1.33), Goodkin said, noting that the hazards of death associated with congestive heart failure and diabetes are of similar magnitude.

HCV infection has also been shown to be associated with increased allograft loss, new-onset diabetes, serious infections, and death among untreated HCV-positive patients who had undergone a kidney transplant.

Treating HCV infection in patients on hemodialysis does work, Goodkin said, pointing to a systematic review that showed a 40% sustained virological response to interferon in those patients, which is comparable to or better than in the general population.

But antiviral therapy can be difficult for patients, which could account for the low treatment rates in patients on hemodialysis, who already have impaired quality of life, he noted.

Interferon is associated with flu-like symptoms, fatigue, depression, and neurological and cardiovascular complications. And ribavirin carries a risk of severe anemia.

Even so, Goodkin said guidelines from KDIGO (Kidney Disease: Improving Global Outcomes) addressed the issue correctly. Those recommendations state that HCV-positive patients who are awaiting a kidney transplant should receive antiviral treatment, whereas treatment in other patients should be considered on a case-by-case basis.

By Michael Smith, North American Correspondent, MedPage Today
Published: November 12, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

SAN FRANCISCO -- A novel hepatitis C virus (HCV) drug targeting genetic material in the liver was safe and well tolerated in a small, dose-finding clinical trial, a researcher said here.

Given as monotherapy, the compound, dubbed miravirsen, induced rapid dose-dependent reductions in the hepatitis C viral load, according to Harry Janssen, MD, of Erasmus Medical Center in Rotterdam, the Netherlands.

The reductions were sustained for more than a month after the end of therapy, Janssen reported at a late-breaker session during the annual meeting of the American Association for the Study of Liver Diseases.

Miravirsen "has the potential to eradicate" hepatitis C virus either alone or as part of an interferon-free regimen, Janssen concluded.

The compound blocks a host microRNA -- miR-122 -- that is critical to hepatitis C accumulation in the liver, Janssen said. MicroRNAs play important roles in gene regulation and expression and Janssen said miravirsen is the first drug to exploit a microRNA target for therapy.

Indeed, of the research presented at the late-breaker session, this study is " the most exciting because it is a whole new class of drug," said Norah Terrault, MD, of the University of California San Francisco, who was not part of the study but who was one of the moderators of the session.

For the study, Janssen said, researchers enrolled 36 patients with the difficult-to-treat genotype 1 of hepatitis C and assigned them to placebo or one of three doses of the drug -- 3, 5, and 7 mg/kg.

The patients, none of whom had been previously treated with pegylated interferon and ribavirin, were given five subcutaneous injections of the drug over four weeks and then followed for another 14 weeks.

The primary endpoint was safety and tolerability, Janssen said, with viral response as a second endpoint. Not all patients have completed the study, so the researchers reported data up to week 10, six weeks after the final dose.

Adverse events, he said, were "very much balanced" among the arms and over all "there were not a lot of side effects seen here." Most such events were mild and none led to stopping treatment, he added.

The only serious adverse event, in a patient receiving the high dose of the drug, was not considered related to treatment, he said.

In all three arms, the drug resulted in a significant drop in hepatitis C RNA levels, compared with placebo. Specifically:

• The low dose (3 mg/kg) led to a 0.57 IU/mL decline in viral load, which was significant at P=0.0334.

• The medium dose (5 mg/kg) yielded a drop of 2.16 IU/mL, which was significant at P=0.007.

• The high dose (7 mg/kg) led to a decline of 2.73 IU/mL, significant at P<0.001.

Although some patients in the low- and medium-dose arms had been allowed to begin treatment with peginterferon and ribavirin three weeks after their last dose of miravirsen, those taking the high dose were not allowed standard therapy until week 10.

Janssen said the drop in viral load seen with the high dose at week 10 "is a pure effect of miravirsen."

The downside of the drug, Terrault told MedPage Today, is that "it has to be given by injection, and that's always a challenging form of treatment."

On the other hand, it appears well tolerated and safe, with good efficacy, so "it might still be part of the mix" of treatment options. "I clearly get the sense it isn't going to be used solo," she said.

The study was supported by Santaris Pharma. Janssen reported financial links with the company and one author was employed by the company.

By Michael Smith, North American Correspondent, MedPage Today
Published: November 13, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

SAN FRANCISCO -- An investigational hepatitis C virus (HCV) drug -- a second-generation protease inhibitor given once a day -- was safe and effective in a phase IIB randomized trial, a researcher said here.

Between 75% and 86% of patients treated with TMC435 had undetectable hepatitis C RNA after 24 weeks of treatment, depending on dose, reported Michael Fried, MD, of the University of North Carolina in Chapel Hill.

In addition, there was no major difference in adverse events between the treatment and placebo arms in the PILLAR (Protease Inhibitor TMC435 trial assessing the optimaL dose and duration as once daiLy Anti-viral Regimen) trial, Fried said at a late-breaker session during the annual meeting of the American Association for the Study of Liver Diseases.

The primary endpoint of the study was the proportion of patients with undetectable hepatitis C RNA at week 72, which was 24 weeks after the end of treatment, Fried said. However, his presentation here focused on what he said was "the most clinically meaningful endpoint," which was the rate of undetectable hepatitis C RNA at week 24.

The researchers enrolled 386 patients with the difficult-to-treat genotype 1 of hepatitis C and randomly assigned them to placebo or one of two doses of TMC435: 75 or 150 mg daily.

All patients were also given standard therapy with pegylated interferon-alfa and ribavirin for at least the first 24 weeks of the study. Depending on response, some patients in the treatment arms stopped the treatment or were given an additional 24 weeks. Patients in the control arm had 48 weeks of interferon and ribavirin.

Within each TMC435 dosing group, patients were randomly assigned to get 12 or 24 weeks of the drug.

• In the 150-mg dosing group, 81% in the 12-week arm and 86% in the 24-week arm reached the same endpoint.

• The differences from placebo were significant at P<0.005, P=0.013, and P<0.001, respectively.

Interestingly, the 75% response in the 24-week, 75-mg arm was not significantly different from the "unexpectedly high" 65% response rate among the placebo patients, Fried said.

A key finding was that between 79% and 86% of the patients receiving the drug qualified for shortened 24-week therapy, "which I think is quite beneficial," Fried said. Of those, he said, between 85% and 96% had undetectable hepatitis C RNA at week 24.

All patients had at least one adverse event, Fried said, with 3.6% of such events leading to study discontinuation in the TMC435 arms, compared with 5.2% in the control arm. The rate of grades 3 and 4 events was similar between the treatment and placebo arms. However, 6.5% of adverse events were judged as serious in the TMC435 group compared with 13% among placebo patients.

Most adverse events, including rash, anemia, and neutropenia, were similar between the arms.

The compound is the "front-runner" in the second generation of protease inhibitors and clinicians are watching its progress closely, according to Norah Terrault, MD, of the University of California San Francisco, who was not part of the study but was one of the moderators of the session at which it was presented.

"This is the next step for us if we are going to use peginterferon and ribavirin," she told MedPage Today. "It is clearly going to offer an advantage over current therapies."

One advantage, she said, is that once-daily dosing -- compared with three times a day for the currently approved drugs -- should improve patient adherence to their treatment regimen.

As well, she added, the "side effect profile looks very good" with no additional burden of rash or anemia.

On the other hand, a range of new drugs is in development and some can be given without interferon. Clinicians may soon be able to choose interferon-free strategies to treat hepatitis C, Terrault said.

SAN FRANCISCO -- Patients with chronic hepatitis C virus (HCV) infection and thrombocytopenia had significant improvement in virologic response when pegylated interferon alpha 2a (Pegasys) was given with eltrombopag (Promacta), results of a randomized trial showed.

Overall, 66% of patients treated with eltrombopag plus peginterferon alpha 2a and ribavirin had an early virologic response compared with 50% of patients who received peginterferon 2a, ribavirin, and a placebo (P<0.0001). Additionally, 23% of the eltrombopag group achieved a sustained virologic response versus 14% of the placebo group (P=0.0064).

Treatment with eltrombopag was associated with an increased time-to-first-dose reduction of peginterferon and with fewer dose reductions, as reported here at the American Association for the Study of Liver Diseases meeting.

"Eltrombopag treatment enabled the introduction of antiviral therapy in 95% of patients who would otherwise be marginal candidates for pegylated interferon 2-alpha therapy," said Nezam H. Afdhal, MD, of Harvard and Beth Israel Deaconess Medical Center in Boston.

"Eltrombopag showed an acceptable safety profile in high-risk patients with cirrhosis," he added.

Preliminary data from a companion study demonstrated similar improvement in early and sustained virologic response when eltrombopag was administered with peginterferon alpha 2b (PEG-Intron).

Patients with advanced liver fibrosis and portal hypertension frequently develop thrombocytopenia, which usually precludes antiviral therapy. Recommended platelet counts for initiation of peginterferon alpha 2a or 2b are ≥90,000/µL and ≥100,000/µL, respectively. Platelet counts commonly decline during peginterferon therapy as a result of myelosuppression.

Eltrombopag is an oral thrombopoietin receptor agonist that increases platelet count by increasing megakaryocyte differentiation and proliferation, Afdhal noted. The drug is approved in the U.S. for second-line treatment of chronic idiopathic thrombocytopenic purpura.

Afdhal reported final results from ENABLE 1 and provided a glimpse of the initial results from ENABLE 2.

ENABLE 1 investigators enrolled patients who had HCV cirrhosis and platelet counts <75,000/µL. The trial had two phases. During the first phase, all patients received open-label eltrombopag at a starting dose of 25 mg, which was titrated to a maximum dose of 100 mg or until a platelet count of ≥90,000/µL was reached.

Patients who achieved the platelet threshold entered the randomized phase of the study, wherein they were allocated 2:1 to receive eltrombopag or placebo, in addition to peginterferon alpha 2a and ribavirin. Patients with HCV genotype 2 or 3 continued treatment for 24 weeks; all others were treated for 48 weeks. The primary endpoint was sustained virologic response.

Afdhal reported that 715 patients entered the open-label phase of the study and had a median baseline platelet count of 59,000/µL, increasing to 89,000/µL by the end of open-label eltrombopag therapy.

Subsequently, 682 patients initiated randomized therapy. They had a median baseline platelet count of about 130,000/µL. After four weeks of treatment, the median platelet count had decreased to 90,000/µL in the eltrombopag arm and to 43,500/µL in the placebo group.

The median platelet count remained >80,000/µL throughout the study in the eltrombopag arm and <50,000/µL in the placebo arm.

In addition to the intention-to-treat analysis, subgroup analyses by HCV genotype showed a consistent difference between groups in favor of eltrombopag. Among genotype 1 patients (N=462), 58% of the eltrombopag group versus 41% of the placebo group had an early virologic response, and 18% versus 10%, respectively, had a sustained virologic response.

Among genotype 2/3 patients, early virologic response occurred in 84% of the eltrombopag group versus 67% of the placebo group and sustained virologic response in 35% versus 24%, respectively.

Afdhal said that 57% of eltrombopag patients required no peginterferon alpha 2a dose reductions, as compared with 30% of the placebo group. Treatment with the thrombopoietin agonist was associated with significant prolongation of the time to first peginterferon dose reduction (P<0.0001).

Adverse events, serious adverse events, and drug-related adverse events occurred in a similar proportion of patients in the two treatment groups. The most common adverse events in both groups were anemia, neutropenia, fatigue, pyrexia, and headache. Thrombotic adverse events occurred in 2% of patients in each group.

A preliminary intention-to-treat analysis of data from ENABLE 2 showed that 62% of eltrombopag-treated patients had an early virologic response compared with 41% of the placebo group (P<0.0001) and sustained virologic response in 19% and 13% of patients, respectively (P=0.020).

Alisporivir, a once-daily drug being developed by Novartis at the forefront of a new class of hepatitis C virus (HCV) compounds known as cyclophilin inhibitors, is showing promise as a component of interferon-free therapy for people with genotype 2 or 3 HCV infection, according to new results from a Phase II study reported in San Francisco at the 62nd annual meeting of the American Association for the Study of Liver Diseases.

Nearly half of all study volunteers using the drug in combination with ribavirin, but without interferon, have undetectable HCV levels after six weeks of treatment, reported Jean-Michel Pawlotsky, MD, of the University of East Paris and his colleagues. In addition, roughly a third of the genotype 2/3 patients in the study had undetectable HCV levels at the six-week mark of therapy with alisporivir alone—use of the drug without either pegylated interferon or ribavirin.

Also known as DEB025, alisporivir works by inhibiting a cellular protein called cyclophilin known to play a role in the reproduction of HCV. The drug is similar to—and actually synthesized from—cyclosporin A, a compound used to suppress the immune system during organ transplants to prevent the body from rejecting the organ. Alisporivir does not, however, suppress the immune system. And because alisporivir targets a cellular protein used by all types of HCV, it may prove to be an effective option against a broad range of HCV genotypes and less susceptible to drug resistance.

The clinical trial reported by Pawlotsky’s team has enrolled about 340 previously untreated people living with genotype 2 or 3 HCV infection. Five groups are being compared in the study. Two groups are receiving alisporivir—either 600 milligrams (mg) or 800 mg once daily—plus ribavirin (400 mg twice daily). A third group is receiving alisporivir (600 mg once daily) plus once-weekly pegylated interferon. A fourth group is receiving standard therapy: pegylated interferon plus twice-daily ribavirin. A fifth group is receiving 1,000 mg alisporivir monotherapy.

Only interim data—all participants in the study remain on treatment—were reported by Pawlotsky’s group. Final results—rates of sustained virologic responses (SVR)s, or viral cures—will be available once therapy is discontinued and study volunteers have been off treatment for 24 weeks.

Six weeks into treatment, 49 percent of those receiving alisporivir plus ribavirin have undetectable HCV levels. In addition, 97 percent of those who had undetectable viral loads at six weeks in the alisporivir/ribavirin groups and had been followed for at least 12 weeks of treatment maintained HCV viral loads below the level of detection.

Also encouraging, 32 percent of those receiving alisporivir alone also have viral loads below the level of detection after six weeks of treatment.

Response rates are thus far similar in the two alisporivir/ribavirin treatment groups—51 percent of those in the 600 mg group had undetectable viral loads at six weeks, compared with 48 percent of those in the 800 mg group. Interim response rates are also similar among those with genotype 2 versus genotype 3 HCV.

Of note, participants receiving alisporivir/ribavirin or alisporivir monotherapy who have detectable HCV levels after four weeks of treatment are receiving add-on pegylated interferon (or pegylated interferon/ribavirin) therapy from week six onward. For those who have met these criteria, as little as two weeks of add-on treatment reduced HCV viral loads to undetectable in more than 85 percent.

Thus far, there has been a low incidence of serious side effects, with rates of adverse events comparable between the treatment groups. A low number of people experienced an increase in bilirubin, a pigment found in the liver, which can cause yellowing of the skin, nails and eyes. Increased bilirubin can also be a sign of liver damage. However, according to Pawlotsky, the bilirubin increases seen in patients receiving alisporivir have not been associated with any other signs of liver damage.

A Phase III study of alisporivir evaluating its safety and effectiveness, when combined with pegylated interferon and ribavirin, for people with hard-to-treat genotype 1 HCV infection is currently under way. Preliminary Phase II data involving this population of patients were reported earlier this year in Berlin at the 46th Annual Meeting of the European Association for the Study of the Liver.

Other studies are being conducted as well, including Phase II evaluations involving people with genotype 1 HCV who tried and failed earlier treatment.

NEW YORK, NY, Nov 16, 2011 (MARKETWIRE via COMTEX) -- The Mount Sinai Medical Center has embarked on a new mission to educate the public about Hepatitis C and urge more Americans to be tested for this "silent killer." While two million people in the US suffer from Hepatitis C, an additional two million are undiagnosed, putting them at risk for devastating long-term effects. Through an important video program, The Mount Sinai Medical Center's Dr. Douglas Dieterich, Professor of Medicine in the Division of Liver Diseases and former Hepatitis C patient, urges people to take charge of their health by getting tested for the virus, even if no symptoms are present.

Did you know?

-- Not all patients are IV drug or intranasal cocaine users. Other ways to contract the virus include: body piercings, tattoos, manicures, pedicures, or even while playing sports such as boxing and rugby

-- The virus can creep along very silently, presenting no symptoms or abnormal liver test results for 30-40 years

-- Hepatitis C is spread by blood-to-blood contact

-- If left undetected, the virus can lead to advanced scarring of the liver, or a condition known as cirrhosis, and eventually cause liver failure or other major complications including liver cancer

-- About 4 times as many people will die in 2020 from Hepatitis C then in 2010

"Many people around the world, probably the majority got it, through the fault of the health care system. They got infected needles from vaccines or other medical devices when they were in the medical world," says Dr. Dieterich.

Along with shattering the stigma surrounding the Hepatitis C virus, Dr. Dieterich wants patients to understand that testing positive for the virus is not a death sentence if caught early. Dr. Dieterich himself contracted the virus in 1977 while attending medical school. He accidentally stuck himself with a needle infected with Hepatitis C and suffered from a rare, but acute reaction. Frustrated with his diagnosis and lack of options to treat it, Dr. Dieterich dedicated his career to studying Hepatitis C and finding effective treatment options for those diagnosed. He was cured in 1998 after an 18-month regimen of daily interferon injections and Ribavirin -- an anti-viral drug that was unavailable at the time of his diagnosis. While he was lucky, he knew there was much more work to be done.

Thanks in part to Dr. Dieterich's commitment to better understanding and treating this virus, we have come much closer to a cure for this disease. Today patients have access to new, FDA-approved protease inhibitors that bring the cure rate to 80 percent.

"If we can treat you, we can cure you almost all of the time. So go get tested before it's too late," Dr. Dieterich says.

The Mount Sinai Medical Center encompasses both The Mount Sinai Hospital and Mount Sinai School of Medicine. Established in 1968, Mount Sinai School of Medicine is one of the leading medical schools in the United States. The Medical School is noted for innovation in education, biomedical research, clinical care delivery, and local and global community service. It has more than 3,400 faculty in 32 departments and 14 research institutes, and ranks among the top 20 medical schools both in National Institutes of Health (NIH) funding and by U.S. News & World Report.

The Mount Sinai Hospital, founded in 1852, is a 1,171-bed tertiary- and quaternary-care teaching facility and one of the nation's oldest, largest and most-respected voluntary hospitals. In 2011, U.S. News & World Report ranked The Mount Sinai Hospital 16th on its elite Honor Roll of the nation's top hospitals based on reputation, safety, and other patient-care factors. Of the top 20 hospitals in the United States, Mount Sinai is one of 12 integrated academic medical centers whose medical school ranks among the top 20 in NIH funding and US News & World Report and whose hospital is on the US News & World Report Honor Roll. Nearly 60,000 people were treated at Mount Sinai as inpatients last year, and approximately 560,000 outpatient visits took place.

Ten years ago, the American Board of Internal Medicine (ABIM)—after much debate—approved the designation of advanced/transplant hepatology as a distinct discipline. Backed by every major gastroenterology and liver society in the country, the specialty was created to reverse a shortage of trained hepatology professionals who were faced with growing numbers of transplant patients.

Now, as the specialty enters its second decade, its proponents once again are looking at ways to revamp training. They say new training paradigms are needed to raise the number of trained liver specialists capable of managing an increasing burden of disease that ranges from obesity-related disorders to patients on transplant lists.

“Training hepatologists is a really big issue now because the burden of liver disease in America is accelerating, and I believe is outstripping the supply of trained individuals to manage it,” said Carl L. Berg, MD, chief of gastroenterology and hepatology, and medical director of liver transplantation at the University of Virginia in Charlottesville.

Most experts point to three factors driving the crunch on hepatology services: growing numbers of patients with liver disease; markedly improved and complex therapies, which have lengthened the lifespan of those with severe disease; and no corresponding rise in the number of physicians with specialized training to care for these patients.

“There are millions of Americans with chronic liver disease, which remains clinically silent until advanced liver disease sets in,” noted Arun J. Sanyal, MD, president of the American Association for the Study of Liver Diseases (AASLD), in the organization’s monthly newsletter last year (available at www.aasld.org/news/archive/022510/Pages/default.aspx). “On the other hand, there are only a thousand or so fully trained hepatologists to serve our communities.

“If progress is to be made in eradication of liver disease and promotion of liver wellness, fixing this manpower shortage must become a national priority,” Dr. Sanyal wrote.

Additionally, the Institute of Medicine called attention to the shortage in January 2010, in a report that highlighted a marked lack of awareness, knowledge and skills among the general medical workforce regarding liver disease.

Historical Hepatology

Although crude forms of hepatology have been around since 2,000 BC (when fortune tellers examined animal livers to foretell the future), modern clinical hepatology has been around for only about 60 years.

The first liver association, the AASLD, was founded in 1950, with its inaugural meeting attended by 12 individuals. Nine years later, British physician Sheila Sherlock set up a liver center at Royal Free Hospital in London, the first of its kind worldwide. For the next 40 years, hepatology fell firmly within the specialty of gastroenterology.

After 1990, liver transplant centers proliferated, and with them, transplant patients. As a result, there was a growing need for dedicated hepatologists to care for these complex patients. In 1999, AASLD members acknowledged the need, saying that advanced/transplant hepatology should be a “distinct discipline” and more physicians trained in the field were necessary.

The emphasis in the new specialty was on liver transplantation rather than broad hepatology, said Bruce R. Bacon, MD, professor of internal medicine at Saint Louis University School of Medicine in St. Louis, in a published interview (Can J Gastroenterol 2007;21:421).

“It was thought that general hepatology remained within the purview of gastroenterology,” Dr. Bacon explained.

Since then, however, the thinking has changed.

“At the present time, it has become increasingly apparent that hepatology should be considered a distinct discipline independent from, but closely allied with, gastroenterology,” Dr. Bacon said.

Contemporary Hepatology

Today, many millions of Americans have liver disease, but the exact figure is unknown. An estimated 4.5 million Americans are infected with hepatitis B and C viruses. Many millions more are affected by non-alcoholic fatty liver disease, although the true incidence remains undetermined; the American Liver Foundation estimates it may be as high as 25% of the adult population. Additionally, an undetermined number of Americans are living with transplanted livers. Today, 6,000 people annually undergo liver transplants, while another 16,000 are on the waiting list.

Compare that to the numbers of liver specialists: About 3,376 specialists in 2007 were dues-paying members of the AASLD. Of them, only half are American-based physicians and only half of those consider the AASLD to be their primary professional society affiliation.

Because the hepatology certification exam has been offered only three times since its creation in 2004, most gastroenterologists who look after liver patients are not board-certified. In fact, only about 2% of practicing gastroenterologists have transplant hepatology certification (Elta GH. Am J Gastroenterol 2011;106:395-397).

Today, 31 accredited hepatology training programs exist in the United States, most of which train only one or two fellows per year. Of these, only 30 to 40 positions are filled annually, said John R. Lake, MD, professor of surgery and medicine, and director of the liver transplant program at the University of Minnesota, in Minneapolis. The remaining spots remain vacant.

For gastroenterology fellows, the reluctance to pursue additional hepatology training can be understandable. Hepatology training adds an extra year, after six years of internal medicine and gastroenterology. Moreover, hepatology work generally pays less than an endoscopy-based gastroenterology practice. The patients require more time, more counseling and undergo fewer procedures.

In the long term, hepatology can be a more taxing specialty for many physicians, said Vinod Rustgi, MD, clinical professor of medicine and surgery at Georgetown University Medical Center in Fairfax, Va.

“It’s very different from procedure-based gastroenterology. Hepatologists end up having to talk to their patients much more than gastroenterologists. It’s a different way of spending the day—you have to interact closely with people,” he said.

Even if gastroenterologists are committed to treating liver disease patients, there’s no real need to pursue the subspecialty certification—they can practice hepatology without pursuing the additional year of training. And no difference exists between what gastroenterologists and hepatologists can do. Both groups perform a full breadth of procedures and their practices often overlap. Nothing would preclude an expertly trained gastroenterologist with hepatology instruction from focusing his or her practice on liver disease patients. The sole exception is directors of liver transplant programs, who require very specific training in hepatology. “But that only applies to 100 people around the country,” said Dr. Berg.

Janice Jou, MD, now a hepatology fellow at Duke University, in Durham, N.C., chose to do the additional year of fellowship to become board-certified. At the time she applied, the fellowship was an easy choice. She was awarded a grant from the AASLD, which made the additional year more financially viable. She loves the patients, their complexity and acuity.

“The advice given to me was [a hepatology fellowship] is what I should do,” said Dr. Jou.

Now, however, she sometimes wonders if she made the right choice. “It’s hard to weigh the delayed gratification of doing another year of fellowship,” she said.

She adds, however, that she believes people who are pursuing an academic career should do the transplant hepatology fellowship. “I do think it is evolving and is likely to change. However, in the current climate I think that if you are serious about an academic career, it is important. This is one of the main reasons that I chose to do the extra year, as I am interested in staying in academics.”

Revamping the Program

There’s no question that the United States needs more trained physicians to treat liver patients. Ironically, it’s the same situation that the gastroenterology community hoped to address a decade ago, with the creation of the advanced/transplant hepatology fellowship and board examination. Now, again, the gastroenterology and liver societies are looking at ways to close the gap between the number of patients who need liver care and the providers available.

Hepatologists by the Numbers

3,444 the number of dues-paying members in the AASLD in 2010

2,335 the number of AASLD members who reside in the United States

1,689 the number of “regular” AASLD members, defined as any physician, scientist or researcher working in the United States, Canada or Mexico who has contributed to knowledge about the liver or biliary tract

31 the number of U.S. programs offering an advanced/transplant hepatology fellowship

30-40 the approximate number of positions filled in advanced/transplant hepatology fellowship programs annually in the United States

7 the number of years of postgraduate training currently required to become a board-certified advanced/transplant hepatologist

4 the number of fellowship grants provided by the AASLD

3 the number of times that the Transplant Hepatology Certification exam has been offered

AASLD, American Association for the Study of Liver Diseases Sources: AASLD News, February 2010; AASLD staff

In 2009, a multisociety task force on gastroenterology training made a number of recommendations on the future of gastroenterology and hepatology training (Am J Gastroenterol 2009;104:2659-2663). Among the recommendations were the creation of a competency-based curriculum, condensed training for transplant hepatologists and enhanced disease-specific training. The ABIM recently gave the go-ahead on the first of those recommendations. This winter, the board approved a pilot program that will test a competency-based curriculum and competency-based assessment program for gastroenterology and hepatology. Trainees will be tested for technical and cognitive milestones through their procedural training, which could effectively short-track their training.

This type of competency-based training is expected to expand over the coming years, said Dr. Lake. The Accreditation Council for Graduate Medical Education (ACGME) already requires residents to demonstrate competency in six core areas. Additionally, similar competency-based programs are being tested around the world in fields outside of gastroenterology. Canadian orthopedic surgeons are testing and implementing a system based on 281 competencies deemed to be of importance in the training of orthopedic surgeons (Wadey VM et al. J Bone Joint Surg Br 2009;91:1618-1622).

Discussions are ongoing to find further ways of condensing the training process for transplant hepatologists. The task force suggested that transplant hepatology training could occur during the standard three-year fellowship, with a tailored exam at the completion of training. Since 1996, gastroenterologists were allowed to subspecialize in areas other than hepatology within their three-year fellowship at certain programs, by tracking elective and research time toward their subspecialty.

“Instead of doing three years of gastroenterology and one year of hepatology, you might be able to customize your three-year program in a way where you would do roughly two years of general gastroenterology and in the final year do full-time hepatology,” said Dr. Berg.

One other option may be to allow hepatologists to train directly after internal medicine and bypass the need for training in gastroenterology. Preliminary discussions were held with the AASLD and ABIM several years ago, but the concept remains theoretical.

All experts who spoke with Gastroenterology & Endoscopy News agreed that hepatologists will never become the sole providers in liver care. “There’s simply not enough of us,” said Dr. Berg.

As liver care becomes more complicated, extra training and expertise will become important for management of some of the problems, he said. But, he added, “I still believe fundamentally that we are going to need our general gastroenterology colleagues to help us because the burden of disease is so great.

“Because the epidemic of obesity in this country—which is associated with fatty liver disease—is so great, that burden is going to just skyrocket over the course of the next decade,” said Dr. Berg.

“If we treat vitamin D deficiency, we can potentially decrease the high rate of osteopenia and osteoporosis in this population, including bone loss related to some of the antiviral therapies” said co-investigator Maya Gambarin-Gelwan, MD, assistant professor of clinical medicine, Weill Cornell Medical College, New York City.

Up to 53% of patients with viral hepatitis–related cirrhosis develop osteoporosis. Given the risk for bone loss associated with low levels of serum 25-hydroxyvitamin D (25[OH]D), investigators set out to determine the prevalence of vitamin D deficiency and insufficiency among patients with HBV and HCV treated at Weill Cornell Medical Center. They defined vitamin D deficiency as serum 25[OH]D less than 20 ng/mL and vitamin D insufficiency as levels between 20 and 30 ng/mL.

Among 2,312 patients with chronic viral hepatitis seen at the center between 2007 and 2009, only 17% (395 of 2,312) had been tested for vitamin D levels. Of those who underwent vitamin D testing, 31% (122 of 395) were vitamin D insufficient and 33% (132 of 395) were vitamin D deficient. The prevalence of vitamin D insufficiency was similar among the 29% (115 of 395) of patients with chronic viral hepatitis who had cirrhosis and those who did not (26% vs. 33%, respectively; P=0.10). However, the difference in vitamin D deficiency among patients with cirrhosis and those without cirrhosis was significant (44% vs. 29%; P=0.01).

Interestingly, vitamin D insufficiency was more prevalent among those infected with HBV than among those infected with HCV (73% vs. 60%, respectively; P=0.01). Although she suspects that ethnicity may play a role in this difference, Dr. Gambarin-Gelwan said that her data set did not include adequate information on ethnicity to draw a conclusion.

Zobair Younossi, MD, MPH, a liver specialist who was not involved in the study, said that prior studies have shown low vitamin D levels tend to be more common in patients with advanced stage fibrosis and cirrhosis. “However, this study shows insufficiency can also be seen in non-cirrhotic patients with hepatitis B and C, and particularly in those with chronic hepatitis B,” said Dr. Younossi, vice president for research, Inova Health System, and chairman, Department of Medicine, Inova Fairfax Hospital, Falls Church, Va.

Dr. Gambarin-Gelwan said that she hopes her research will spur clinicians to routinely monitor vitamin D levels in patients with chronic HBV and HCV infection. She said the small percentage of patients who were screened for vitamin D levels demonstrates that “gastroenterologists and hepatologists are paying too little attention to vitamin D levels.”

San Francisco — A human monoclonal antibody developed by MassBiologics of the University of Massachusetts Medical School (UMMS) given to patients with chronic hepatitis C virus (HCV) infection undergoing liver transplantation significantly suppressed the virus for at least a week after transplant and delayed the time to viral rebound. Results from a randomized, double-blind, placebo-controlled, phase 2 study were presented this week at The Liver Meeting®, the annual meeting of the American Association for the Study of Liver Diseases, in San Francisco.

"The challenge for patients with end-stage liver disease from HCV is that a transplant is not a cure. Because the virus remains in the blood stream, the new liver eventually becomes infected with the hepatitis C virus," said Deborah C. Molrine, MD, deputy director of clinical and regulatory affairs at MassBiologics. "These results show that a human monoclonal antibody targeting the hepatitis C virus can significantly reduce viral loads in infected patients who receive donor livers and moves us one step closer to clearing the virus so the new liver doesn't become chronically infected."

Five hospitals enrolled patients in the trial —Massachusetts General Hospital, Beth Israel Deaconess Medical Center, both in Boston, Lahey Clinic in Burlington, Massachusetts, Yale-New Haven Hospital in Connecticut and Mount Sinai Hospital in New York City. Patients enrolled in the study were treated with a total of 11 intravenous infusions of either the human monoclonal antibody, designated MBL-HCV1, prior to, during, and after surgery or a placebo (salt solution). The first three infusions were administered on the day of transplantation followed by a daily infusion in the first week following surgery and a final infusion 14 days after transplant. Of the 11 patients enrolled in the first part of the trial, six received the MBL-HCV1 antibody. "The commitment of the transplant team at each site working with study investigators ensured the delivery of the multiple infusions according to schedule and all infusions were well tolerated by the patients. The infusions did not add to any patient's length of stay in the hospital." said Fredric Gordon, MD, medical director of liver transplantation at Lahey Clinic Medical Center.

The group of patients who received the monoclonal antibody had a significantly greater reduction in viral load from pre-transplant levels at days three through six post-transplant compared to patients who received the placebo. One patient's viral load dropped below the detection limit starting at day two after transplant and didn't have a viral rebound until day 35.

"Because the HCV virus is prone to mutations, patients develop variants of the virus that can escape from the effect of a single type of treatment," said Molrine. "In the next phase of the study, we plan to combine the monoclonal antibody with another HCV antiviral agent to see if the activity of two drugs against the virus results in further suppression, if not clearance, of the virus."

HCV damages the liver and is the leading indication for liver transplantation, diagnosed in about half of the 6,000 patients who receive liver transplants each year in the United States. According to the US Centers for Disease Control and Prevention, 3.2 million Americans are chronically infected with HCV and approximately 10,000 die annually of the disease. Globally, as many as 170 million people are estimated to suffer from HCV infection.

For patients with end-stage liver disease from HCV infection, liver transplantation is the only option. While it can be a life-saving treatment, transplantation does not cure the disease. In nearly all cases, the patient's new liver is eventually infected by HCV because the virus remains in the patient's bloodstream during surgery. The course of recurrent HCV disease is accelerated after transplantation and up to 20 percent of transplant patients develop cirrhosis within five years. Unfortunately, the standard antiviral drugs currently used to treat HCV prior to the onset of end-stage liver disease are poorly tolerated after liver transplantation, leaving these patients with few options.

"The ability to prevent allograft infection using strategies such as immunoprophylaxis would have an enormous impact on outcomes of liver transplantation for HCV," said Raymond T. Chung, MD, director of hepatology at Massachusetts General Hospital.

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About MassBiologics

MassBiologics, also known as the Massachusetts Biologic Laboratories, is the only non-profit FDA- licensed manufacturer of vaccines and other biologic products in the United States. MassBiologics produces 30 percent of the US tetanus/diphtheria vaccine supply. In addition to the HCV program, MassBiologics has discovered and developed human monoclonal antibodies to severe acute respiratory syndrome (SARS), and to Clostridium difficile (C. difficile), which has shown efficacy in a Phase 2 clinical trial, and to rabies which will be starting Phase 2 clinical trial soon in collaboration with the Serum Institute of India. MassBiologics traces its roots to 1894, and since then has maintained a mission to improve public health through applied research, development and production of biologic products. MassBiologics has been a part of the University of Massachusetts Medical School since 1997.

About the University of Massachusetts Medical School

The University of Massachusetts Medical School has built a reputation as a world-class research institution, consistently producing noteworthy advances in clinical and basic research. The Medical School attracts more than $307 million in research funding annually, 80 percent of which comes from federal funding sources. The work of UMMS researcher Craig Mello, PhD, an investigator of the prestigious Howard Hughes Medical Institute (HHMI), and his colleague Andrew Fire, PhD, then of the Carnegie Institution of Washington, toward the discovery of RNA interference was awarded the 2006 Nobel Prize in Physiology or Medicine and has spawned a new and promising field of research, the global impact of which may prove astounding. UMMS is the academic partner of UMass Memorial Health Care, the largest health care provider in Central Massachusetts. For more information, visit http://www.umassmed.edu/.

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